Vagal Nerve Stimulation to Treat Disorders of Consciousness (REVELATION)

November 6, 2024 updated by: University of Milano Bicocca

Transcutaneous Vagal Nerve Stimulation to Treat Disorders of Consciousness

This interventional study aims to assess the clinical efficacy of transcutaneous auricular vagal nerve stimulation (taVNS) against sham stimulation on the recovery of consciousness in patients with disorders of consciousness. The main question it aims to answer is: will taVNS improve patients' behavioral scores or will it produce an improvement in the diagnosed level of consciousness? Researchers will compare the results with non-stimulated unconscious patients to see if the re-gain of consciousness is faster in the treated group.

Participants will undergo taVNS stimulation using the Parasym device or sham stimulation will be applied from the time of enrolment.

Active stimulations will be carried out for 60 minutes twice daily during the acute phase and daily during the rehabilitation phase.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a prospective, multicentric, double-blind, parallel, 2 arms, randomized controlled trial that compares active taVNS stimulation against sham stimulation.

The primary objective of this study is to assess the clinical efficacy of transcutaneous auricular vagal nerve stimulation (taVNS) against sham stimulation on the recovery of consciousness in patients with disorders of consciousness (DoC), including comatose patients, unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS). The hypothesis is that taVNS will improve patients' behavioral scores compared to sham stimulation, as measured by an improvement of at least 3 points in the Coma Recovery Scale-Revised score (CRS-R) or an improvement in the diagnosed level of consciousness, measured at 3 months post-randomization, coinciding with the end of stimulation.

As a secondary objective, we will investigate whether:

  1. taVNS is effective in achieving a faster time to recovery of consciousness in DoC patients compared to controls;
  2. the CRS-R score differs in the two groups at 3 and 6 months post-randomization;
  3. the persistence of improvements in the treated group also at 6 months post-randomization.

taVNS stimulation using the Parasym device or sham stimulation will be applied from the time of enrolment (between 7 to 15 days since admission in ICU) un-til day 90 post-enrolment.

Active stimulations will be carried out daily for 60 minutes twice daily during the acute phase and daily during the rehabilitation phase The stimulation waveform includes trains of pulses with widths of 200 µs and repetition rate of 20 Hz (Nurosym proprietary waveform); current delivery will be set at a prede-fined therapeutic level below 0.25 W/cm² (Watts per centimeter squared), that being the defined risk threshold for a thermal burn. The device adjusts stimulation intensity at 0.8 mA steps; the starting intensity will be set at 16 mA (level 20).

Assuming a delta of response of 30% at 3 months between the experimental and the sham group and considering a 1:1 randomization ratio and a 20% drop-out rate, a sample of 53 patients per group (106 in total) is required to reach a power of 80% (alpha=5% and two-sided test on proportion).

Study Type

Interventional

Enrollment (Estimated)

106

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
    • BG
      • Bergamo, BG, Italy
        • ASST Papa Giovanni XXIII
        • Contact:
        • Contact:
          • Paolo Gritti, MD
    • BS
      • Brescia, BS, Italy
        • ASST degli Spedali Civili
        • Contact:
        • Contact:
          • Francesco Rasulo, MD, Professor
    • CO
    • GE
      • Genova, GE, Italy
        • Ospedale Policlinico San Martino IRCCS
        • Contact:
        • Contact:
          • Chiara Robba, MD, Professor
    • MB
      • Monza, MB, Italy, 20900
        • Fondazione IRCCS San Gerardo dei Tintori
        • Contact:
        • Contact:
          • Alberto Addis, MD
    • MI
    • PD
      • Padova, PD, Italy
    • PR
      • Parma, PR, Italy
        • Azienda Ospedaliero Universitaria di Parma
        • Contact:
        • Contact:
          • Edoardo Picetti, MD
    • RM
      • Roma, RM, Italy
        • Fondazione Policlinico Universitario Agostino Gemelli Irccs
        • Contact:
        • Contact:
          • Anselmo Caricato, MD, Professor
    • Virginia
      • Varese, Virginia, Italy
        • Asst Sette Laghi Ospedale di Circolo e Fondazione Macchi
        • Contact:
        • Contact:
          • Luca Cabrini, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18 years old;
  • any acquired cerebral damage of any known etiology;
  • diagnosis of coma, UWS, or MCS with the corresponding basal CRS-R (Coma Recovery Scale-Revised) score performed during the screening period from 7 to 15 days since admission in ICU;
  • intact ear skin;
  • availability of the device.

Exclusion Criteria:

  • Patients with severe hemodynamic, respiratory, infectious, or neurological instability requiring active treatment requiring mechanical ventilation or vasoactive drugs or pending acute neurosurgical interventions;
  • Need for deep sedation, including general anesthetics (e.g., propofol) or a combination of central-acting sedatives;
  • Documented pregnancy;
  • Active implant (e.g., pacemaker, cochlear implant);
  • History of previous serious neurological disability before the brain injury;
  • Seizures or status epilepticus as cause sustaining the disorder of consciousness;
  • Patients already enrolled in another ongoing interventional trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Stimulated group

taVNS stimulation using the Parasym device or sham stimulation will be applied from the time of enrolment (between 7 to 15 days since admission in ICU) until day 90 post-enrolment.

Active stimulations will be carried out daily for 60 minutes twice daily during the acute phase and daily during the rehabilitation phase The stimulation waveform includes trains of pulses with widths of 200 µs and repetition rate of 20 Hz (Nurosym proprietary waveform); current delivery will be set at a predefined therapeutic level below 0.25 W/cm² (Watts per centimeter squared), that being the defined risk threshold for a thermal burn. The device adjusts stimulation intensity at 0.8 mA steps; the starting intensity will be set at 16 mA (level 20).
Device: transcutaneous auricular vagal nerve stimulation

Participants will be randomly assigned to receive either taVNS applied to the tragus of the ear or a sham stimulation from the time of randomization for 90 days.

Active simulations will be carried out daily using the Parasym device for 60 minutes twice daily during the acute phase (two sessions, one in the morning and one in the afternoon), and once daily (single session) during the rehabilitation phase. The stimulation waveform includes trains of pulses with widths of 200 µs and repetition rate of 20 Hz (Nurosym proprietary waveform); current delivery will be set at a predefined therapeutic level below 0.25 W/cm² (Watts per centimeter squared), that being the defined risk threshold for a thermal burn. The device adjusts stimulation intensity at 0.8 mA steps; the starting intensity will be set at 16 mA (level 20).

Other Names:
  • Experimental arm
Sham Comparator: Control group
The Parasym device will be positioned on the patients as for the stimulated group (60 minutes twice daily during the acute phase - two sessions, one in the morning and one in the afternoon), and once daily (single session) during the rehabilitation phase but it won't be switched on.
Device: Sham (No Treatment)
The sham stimulation involves placing the electrode on the same site without delivering any electrical current. The device will be applied to the tragus without electrical current delivered from the time of randomization for 90 days (i.e., the time of randomization coincides with the first stimulation session).
Other Names:
  • control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of response to stimulation
Time Frame: 90 days post-randomization

A response is defined as an increase of at least 3 points in the Coma Recovery Scale-Revised (CRS-R), or a clinical change in the diagnosed level of consciousness: from coma to unresponsive wakefulness syndrome (UWS), from UWS to minimally conscious state (MCS), or emergence from MCS.

Clinical markers for the diagnostic improvements are derived from the CRS-R scale:

  • The transition from coma to UWS will be defined as the appearance of eyes opening.
  • The MCS minus state will be defined by the appearance of visual pursuit, object localization, automatic motor responses, or object manipulation.
  • The MCS plus will be defined by the appearance of non-functional intentional communication, intelligible verbalization, object recognition, or movement to command.
  • Emergence from MCS will be defined by the appearance of functional accurate communication or functional object use.
90 days post-randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
taVNS effectiveness
Time Frame: 90 days post-randomization
To evaluate if taVNS is effective in achieving a faster time to recovery of consciousness in DoC patients compared to controls.
90 days post-randomization
CRS-R score difference
Time Frame: 90 days and 180 days post randomization
To evaluate if the CRS-R score differs in the two groups at 3 and 6 months post-randomization.
90 days and 180 days post randomization
Efficacy duration
Time Frame: 180 days post-randomization
To evaluate if improvements persist in the treated group
180 days post-randomization

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Responders phenotype
Time Frame: 180 days
To evaluate the phenotype of clinical responders by identifying factors based on patient demographics, and clinical and functional impairments that may be associated with treatment responsiveness, if any.
180 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Milano Bicocca

Investigators

  • Principal Investigator: Giuseppe Citerio, MD, Full Professor, University of Milano Bicocca
  • Study Director: Alberto Addis, MD, Fondazione IRCCS San Gerardo dei Tintori

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 1, 2025

Primary Completion (Estimated)

February 1, 2028

Study Completion (Estimated)

June 1, 2028

Study Registration Dates

First Submitted

November 6, 2024

First Submitted That Met QC Criteria

November 6, 2024

First Posted (Estimated)

November 8, 2024

Study Record Updates

Last Update Posted (Estimated)

November 8, 2024

Last Update Submitted That Met QC Criteria

November 6, 2024

Last Verified

November 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • REVELATION

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Patients recruited in this study cannot provide informed consent at the time of recruitment. The responsible research staff will act as Consultee and consent-eligible patients after discussion with the next-of-kin.

If the patient has a Power of Attorney or a Legal tutor, he/she will act as a Consultee and will be asked to consent/decline participation in the study on legal behalf of the patient.

If patients have an Advance Decision Plan, including participation in research studies, the Plan will be respected, and recruitment pursued/abandoned accordingly.

At follow-up, patients who have regained capacity will be asked to provide Informed Consent and will be given the possibility to:

  • Provide Informed Consent for the acute data and follow-up.
  • Deny research participation and request destruction of acute data collected. Furthermore, participants, their legal representatives, or substitute decision-makers may withdraw consent and discontinue participation at any time during the study.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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